A Structural Perspective of the Role of IP6 in Immature and Mature Retroviral Assembly

Abstract

The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles. However, the molecular details underlying this effect have been determined only recently, with the identification of the IP6 binding site in the immature Gag lattice. IP6 also promotes formation of the mature capsid protein (CA) lattice via a second IP6 binding site, and enhances core stability, creating a favorable environment for reverse transcription. IP6 also enhances assembly of other retroviruses, from both the Lentivirus and the Alpharetrovirus genera. These findings suggest that IP6 may have a conserved function throughout the family Retroviridae. Here, we discuss the different steps in the viral life cycle that are influenced by IP6, and describe in detail how IP6 interacts with the immature and mature lattices of different retroviruses.

HIV-2 Immature Particle Morphology Provides Insights into Gag Lattice Stability and Virus Maturation

“…In addition, cell and biochemical data indicate that IP6 is a critical factor in capsid self-assembly. HIV-2 contains conserved lysine residues found within two rings of six lysine residues at the C-terminal end of CA CTD (K292 in HIV-2) and SP1 (K361 in HIV-2) [28, 30, 31].…”

Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding

“…The C-terminal domain (CA CTD ) engages in the dimeric and trimeric interactions that join hexamers together into a lattice. The small molecule inositol hexakisphosphate (IP 6 ) is known to act as an assembly factor for both immature and mature HIV-1 CA lattices (10, 11). In the mature lattice, IP 6 coordinates R18 in the central CA NTD pore (12), where it greatly increases capsid stability (13).…”

Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

“…It serves to recruit nucleotides required for reverse transcription and as a binding site for inositol hexakisphosphate (IP6), a metabolite present at concentrations of ∼40–50 μM in human cells (Bunce et al, 1993; Letcher et al, 2008; Veiga et al, 2006). IP6 is specifically packaged into immature virions during assembly in producer cells, leading to a ≥10–fold enrichment, and its interaction with the central hexamer pore is essential for the assembly and stability of the capsid (Dick et al, 2018; Mallery et al, 2018; Obr et al, 2021; Sowd and Aiken, 2021). The central pore has also been implicated in the capsid’s interaction with microtubule-based motor proteins (Huang et al, 2019).…”